Frontiers and hotspots in hand, foot, and mouth disease research during 2006 to 2023: A bibliometric and visual analysis

Background: Enteroviruses-infected hand, foot, and mouth disease (HFMD) seriously threatens human health. This study aimed to analyze the research status, hotspots, and frontiers of HFMD. Methods: Publications on HFMD between January 1, 2006, and January 31, 2023, were retrieved from the Web of Science Core database. Bibliometric tools, including CiteSpace, VOSviewer, R package “Bibiometrix,” SCImago Graphica, and Charticulator, were utilized to analyze and visualize the data. Results: A total of 1860 articles from 424 journals, involving 8815 authors from 64 countries and 1797 institutions were analyzed. The number of studies on HFMD has shown an increasing trend over the past 18 years, with an annual increase observed since 2006, which is particularly prominent after 2010. Research in this field has centered on the Asian region. Notably, the research hotspots were mainly focused on vaccines, epidemiology, and pathogenesis of HFMD. Among the researchers in this field, Zhang Yong emerged as the most prolific author, while Xu Wenbo had the most significant influence. The Chinese Academy of Sciences was the most productive institution, and China was the most productive country for HFMD research. Conclusion: By bibliometric analysis, researchers in the HMFD field can efficiently identify and visually represent their research focus and limitations. In the future, it is crucial to maintain ongoing surveillance of HFMD outbreaks and their pathogenic changes. Additionally, future research should extensively explore the molecular mechanisms underlying Enteroviruses-induced HFMD with a focus on developing vaccines and therapies.


Introduction
Hand, foot, and mouth disease (HFMD) is an infectious disease caused by enteroviruses that primarily affects children under 5 years of age.Since 2008, HFMD has been classified as a Class C infectious disease in China. [1]Although most cases of HFMD are mild and self-limiting, some children may develop severe complications.Usually, HFMD has an incubation period of 2 to 10 days, and its symptoms include fever and rash on the hands, feet, mouth, and buttocks. [2]he progress of HFMD can be divided into 5 stages.Most patients go through the first stage and recover within 1 week.However, some patients may have severe symptoms, such as high fever, nervous system involvement, and abnormal respiratory or circulatory function.Atypical manifestations may also occur, and differential diagnosis is necessary to distinguish HFMD from other diseases.Moreover, recent studies have found that patients who have recovered from severe YL and YR contributed equally to this work.

This work was supported by the Scientific Projects of Health Commission of Hubei Province (Grant No. WJ2021M089), Research Development Foundation of the Hubei University of Science and Technology (Grant No. 2021-23GP04), Research Development Foundation of the Hubei University of Science and Technology -Specialization in School of Stomatology and Ophthalmology (Grant No. 2021WG02) and Specialization in Xianning Medical College (Grant No. 2023YKY07), Innovative research team project of the Hubei University of Science and Technology (Grant No. 2023T09), and Training Program of Innovation and Entrepreneurship for Undergraduates of Hubei Province (Grant No. S202310927015/ S202310927034).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.Ethical approval was not sought for the present study because there were no animals or human participants involved in this study.HFMD may experience severe long-term neurological complications. [2]Therefore, HFMD has emerged as a major public health concern.
Human enteroviruses (EVs) cause HFMD and belong to the Enterovirus genus of the Picornaviridae family.Since 1999, these viruses have been classified into 4 categories based on their molecular, biological, and genetic characteristics.More than 100 types of EVs have been identified around the world.Enterovirus 71 (EV71) and Coxsackievirus A16 are the most common causes of HFMD.Currently, some other EVs, such as CVA6 and Coxsackievirus A10 (CVA10), have also played an important role in HFMD outbreaks.The recent identification of Tomato flu, an illness similar to HFMD caused by an Enterovirus in India, has rekindled people's interest in HFMD outbreaks. [3]Although these Enteroviruses can trigger a strong immune response, there is little cross-immunity between different serotypes. [2]Therefore, there is an urgent need to develop a multivalent vaccine to enhance protection against various EV serotypes and reduce the risk of HFMD outbreaks. [4]Thus, there are still many unresolved issues regarding HFMD.
Bibliometrics employs mathematical and statistical techniques to collect data on publishing rates, characteristics, and patterns in a specific field.Through analyses of authors, co-occurrence, and citations, we can show research trends and status in specific fields.This type of research can map the field of knowledge and determine the productivity of researchers, internal collaboration, and distribution, as well as that of affiliated institutions and journals.Additionally, bibliometric research revealed research hotspots in a field and possible future development directions.This study aimed to summarize the research status and development stage of HFMD and its main pathogenic viruses, including epidemiology, molecular biology, clinical treatment and diagnosis, and the development and application of vaccines to provide suggestions for clinical treatment and scientific research.

Data collection and search strategy
The data for this study were obtained from the Web of Science Core Collection (WoSCC), which includes 6 indexes: Science Citation Index EXPANDED (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Arts & Humanities Citation Index (AHCI), Emerging Sources Citation Index (ESCI), Current Chemical Reactions (CCR-EXPANDED), and Index Chemicus (IC).The search was conducted from January 1, 2006, to January 31, 2023, using the search query Topic Sentences (TS) = ("Hand, foot, and mouth disease "OR" HFMD ") AND TS= (" Enterovirus "OR" coxsackievirus "OR" echovirus ").Only journal articles and reviews written in English were retained.A total of 1860 articles were included in the final analysis.

Bibliometric analysis
The bibliometric tools, including CiteSpace, VOSviewer, R package "Bibiometrix," and SCImago Graphica, were used for data analysis and visualization.According to previous methods, we exported all records from the WoSCC database in plain text format and saved them as "download_xxx.txt"files. [5,6]ubsequently, these files were imported into CiteSpace 6.2.R4 software to identify critical scientific information, including keyword bursts, reference bursts, and journal dual-map overlays. [7,8]The parameters of the CiteSpace software included the time span from January 1, 2006, to January 31, 2023, with 1 year per slice.Node types included keywords and references.The selection criteria were set to the top 50 for each slice, while the other settings remained the default.The parameters in VOSviewer were set as follows: select "association strength" as the standardization method, and set the thresholds as at least 5 publications in countries/regions, at least 30 publications in institutions, at least 20 publications by author, publications, or co-citations by journal, at least 50 co-occurring keywords, and at least 100 citations in each publication. [9,10]The data exported from the VOSviewer analysis were imported into Charticulator (https://donghaoren.org/charticulator/index.html) and SCImago Graphica to optimize the visual outputs while maintaining their original contextual meanings.Charticulator was used to enhance author co-occurrence networks and journal cooccurrence networks, while SCImago Graphica perfected countries' analysis and keyword co-occurrence analysis. [11,12]urthermore, we used the R 4.4.2package Bibiometrix to map the annual scientific output and analyze the geographical distribution of publications over a period of time. [13]Finally, Microsoft Excel and Word were used for data sorting and statistics, and tables and H-index of the top 10 countries were made, as well as the chart of each article cited and the total cited.

Basic information
According to the screening strategy shown in Figure 1, we obtained 1860 HFMD-related publications for further analysis.Of these 1860 articles, 93% were articles, while the rest were listed in the reviews (n = 134, about 7%).All the included articles were cited 44,206 times, each article was cited 23.77 times, and the H-index was 87.The articles were published in 64 countries/regions, 1797 institutions, 8815 authors, and 424 journals.

Annual publication trends
In order to analyze the annual publication trends from 2008 to 2016, as shown in Figure 2A, the global research on HFMD shows a consistent growth from 2008 to 2016.Following this period, the publication output was maintained at a stable level until 2018, reaching a peak of 190 articles published in 2019.This remarkable increase can be attributed to the rising global epidemic of HFMD, especially in China, Vietnam, and Thailand, where the incidence and mortality of HFMD are staggering.As a result, an increasing number of researchers are forced to undertake relevant research and publish their findings.Nevertheless, since 2021 and 2022, the number of publications has exhibited a declining trend, but it is expected to reach a stable level or may increase in the future.Figure 2B demonstrates the annual changes in the number of HFMD-related publications for the top 10 countries with the highest publication output.Since 2006, the number of publications on HFMD in China has greatly increased, surpassing those in other countries.Furthermore, this trend is expected to continue to develop steadily after 2022.In contrast, the output of publications in other countries remains stable, though low.As the largest country in Asia and the area most seriously affected by HFMD, China has experienced a series of HFMD outbreaks since the first outbreak of HFMD in 2006.This has prompted domestic researchers to do more research on the characteristics and effects of this disease.

Geographical distribution of publications
In total, 64 countries conducted HFMD research.We calculated the H-index, average citations, and total citations of the top 10 countries with the largest number of articles published from 2006 to 2023 (Fig. 3A).China, the United States of America (USA), and the United Kingdom (UK) were the top 3 countries with the highest H-index, while each article in the UK, Australia, and Malaysia had the highest average citations (Fig. 3B).The countries with the highest total citations were China, the USA, and the UK, as shown in Figure 3C. Figure 3D shows the map of collaborations between countries with at least 10 publications.Geographically, cooperation in virology research is spread worldwide, and research locations are concentrated in Asia, while China is in the leading position in virology research.China has collaborated with several countries, with collaboration with the USA being the most substantial.Countries of different colors on the map have established cooperative relations, while countries of the same color have stronger and more remarkable cooperative relations with each other.In particular, China has established cooperative relations with the USA, Malaysia, the UK, Australia, and Singapore.

Visual analysis of institutions and authors
The visualization of the institutions is presented in Figure 4A, which shows the cooperation heat map between the institutions.We presented a total of institutions with more than 30 articles.The heat map illustrates that Fudan University closely cooperated with the Chinese Center for Disease Control and Prevention, and the same close link was also observed between the Chinese Academy of Medical Sciences and Peking Union Medical College.The deepest color indicates these institutions made great contributions.Table 1 shows that among the top 10 institutions that published the most publications, the Chinese Academy of Sciences ranked first with 148 articles, followed by the Chinese Center for Disease Control and Prevention (115), and the Chinese Academy of Medical Sciences (106).Among the top 10 institutions, the Chinese Center for Disease Control and Prevention had the highest total number of citations, while the University of Oxford had the highest average number of citations.The H-index is frequently employed as an effective index to assess academic influence, whereas Total Linkage Strength (TLS) indicates the strength of collaborative relationships. [14,15]The institution with the highest H-index and TLS was the Chinese Center for Disease Control and Prevention.This demonstrates the potential influence of the Chinese Center for Disease Control and Prevention.8 of the research. [16]Figure 4B shows Zhang Yong has established close  cooperative relationships with Yang Dongmei, Xu Wenbo, and Shuangli Zhu, among other authors, and the establishment of their mutual cooperative relationships intertwine to form a network.

Visual analysis of journals
When analyzing the top 10 journals that published the most articles, we found that they contributed to 33.4% of the articles in this field (Table 3).Except for PLOS ONE and Scientific Reports, the top 10 journals publishing the most articles related to HFMD were all within the field of virology research.PLOS ONE had significantly more publications than other journals, making the largest contribution to HFMD research.The Journal of Medical Virology had the highest impact factor (IF) among the top 10 journals (IF = 12.7 in 2023), indicating higher standards and more persuasive data in journal articles.The Journal of Virology had the highest H-index, indicating its significant influence on HFMD.These journals were mainly concentrated in the third quarter and played a vital role in disseminating research results.Among the top 10 published journals, 4 were from the UK, 3 were from the USA, and the rest were from Austria, the Netherlands, and Switzerland.This demonstrates that the UK and USA are concerned about the field of HFMD.
Figure 5A visualizes journals that have published more than 20 articles and cited more than 20 articles, which is consistent with Table 3.The length of the rectangles at the bottom of Figure 5A represents the number of articles published in the indicated journal, and the thickness of the connecting line represents cooperation strength.Figure 5B reveals the core and edge positions of journals with varying article counts.Figure 5C covers a biplot of journals that denotes their topic distribution and research field coverage.The left side of the graph represents the citing journal and the right side of the graph represents the cited journal.The connection paths represent the reference paths, and the linewidth reflects the citation frequency on the z-score scale.The orange and green paths reveal the frequent citations of molecular biology and genetics in molecular biology immunology, medicine, and clinical journals.

Keywords analysis
In this study, we analyzed 4451 keywords in 1860 articles, focusing on keywords that appeared at least 50 times.As shown in Figure 6A, the co-occurrence map reveals 3 clusters: the orange cluster mainly involves vaccine research of HFMD, including 11 keywords; the blue cluster mainly focuses on epidemiological research, including 18 keywords; and the green cluster is mainly related to the pathogenesis of HFMD, including 22 keywords.Items in a cluster have a high homogeneity. [17]Over the years, these fields have become the main focus of HFMD research.We also identified the top 25 keywords with the strongest burst intensity (Fig. 6B), which can help researchers identify research hotspots and determine trends.Taiwan (China) had the highest burst intensity (28.32) and duration (8 years), followed by Enterovirus A71 with a burst intensity of 15.83 and a duration of 5 years, where the thick red line represents the start and end of the outbreak.The keywords focused on the pathogens, clinical manifestations,

Table 1
The top 10 institutions ranked by number of publications related to HFMD.epidemiology, and molecular biology of HFMD, which indicates that continuing to pay attention to virological, epidemiological, and clinical studies will remain hot topics in future research.

Article and citation analysis
As shown in Table 4, the most cited article is "Virology, Epidemiology, Pathogenesis, and Control of Enterovirus 71" published by Solomon Tom in 2010, and it was cited 896 times.
In this study, the features of EV71 were systematically and comprehensively reviewed, which became the standard reference in the field.The article with the highest linkage strength is connected to other articles and has been frequently cited in subsequent research.Seven of the top 10 cited articles were published in Q1 journals, indicating that IF and credibility were high.Among these, the New England Journal of Medicine had the highest IF (158.5) in Q1, with an H-index of 933.The article entitled "Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China" was mainly conducted in a randomized, double-blind, placebo-controlled, and multicenter trial.It ultimately proved the efficacy of the EV71 vaccine in preventing HFMD or herpangina associated with EV71 in infants and  young children, providing important reference value for EV71 prevention and gaining widespread attention in subsequent research. [18]In Figure 7, the blue line represents the time interval and the red line represents the burst duration.The first cited explosion occurred in 2013 and originated from an article published in 2010.The last 3 citation bursts occurred in 2020 and are still in progress.

Discussion
In this study, the literature related to HFMD published between 2006 and 2023 was analyzed by bibliometric methods.A systematic analysis was conducted on the publication trends, countries, institutions, authors, journals, keywords, and articles.Over the past 18 years, the development and spread of HFMD have seriously threatened the health and lives of children.This has led to an increasing number of researchers and institutions Since 2006, the number of articles related to HFDM has increased by more than 10 times compared to that in 2019 (Fig. 2).There are multiple reasons for this trend.First of all, with the increase in diagnosed cases of HFMD, global attention on the prevention and control of HFMD has also increased.Secondly, the development of virology and molecular biology makes the research on HFMD viruses more in-depth.In addition, public awareness of disease prevention has been continuously enhanced, and the acceleration of population movement has also led to the continuous variation of viral strains, which has promoted the research of HFMD in countries all over the world.Therefore, the number of articles related to HFMD has shown an increasing trend over the years.Among the 64 countries participating in the HFMD research, China is the most productive and influential country, which plays a significant role in HFMD research (Fig. 3).Owing to the widespread occurrence of HFMD in China, many human and financial resources have been allocated for this research.Therefore, there are prolific authors and institutions in China, resulting in a very high output of articles.Through extensive research, China has accumulated a lot of data and experience and has a certain degree of understanding of the pathogenesis, transmission, prevention, and treatment of the disease.Meanwhile, China actively participates in international cooperation and communication, which further enhances its influence. [19]International cooperation facilitates the accurate exchange of information, which can more directly promote the output of articles and research results, identify different pathogenic viruses and mutant strains in time, and exchange diagnosis and treatment suggestions in time.However, although China has the highest number of published articles, the average citations per article are lower than those of the UK, Australia, and Malaysia, indicating that some individual publications in China have a lower impact.More influential and high-quality publications are needed, and virus research in China should be further strengthened to achieve this goal.From a global perspective, the establishment of cross-national and regional cooperation is conducive to the dissemination of information and the exchange of science and  technology, which is conducive to understanding and combating unknown areas related to viruses as soon as possible.With the continuous expansion of virus research around the world, more and more research institutions are involved.We can better understand the disease information, overcome difficulties, and share information on a global scale.According to Figure 4, the most prolific institutions and authors are all from China, which proves its role and contribution as a major country.The Chinese Academy of Sciences and the Chinese Center for Disease Control and Prevention are the most prolific and influential institutions (Table 1).As the foremost academic institution in China for natural sciences, the Chinese Academy of Sciences has played a vital role in publishing a wide range of articles.The Chinese Center for Disease Control and Prevention is mainly engaged in disease prevention and control, emergency response to public health emergencies, etc, and plays an irreplaceable role in protecting citizens' health. [20]Although the number of articles published by the Chinese Center for Disease Control and Prevention is less than that of the Chinese Academy of Sciences, their influence is much stronger than that of the Chinese Academy of Sciences.Although the number of publications, H-index, and TLS of the University of Oxford were not as high as those of the Chinese Center for Disease Control and Prevention and the Chinese Academy of Sciences, the average number of citations of each article was the highest.This also indirectly reflects an institution's influence, indicating that an institution's influence cannot be judged only by the quantity of its publications.When investigating the influence of an institution, we must consider the quality and quantity of its articles.This indicates that there are other factors besides the number of publications in determining the impact of articles, and research institutions should focus more on article quality and research innovation.The difference in influence between China's Disease Prevention and Control Centers and the Chinese Academy of Sciences in terms of publishing HFMD-related articles can also be attributed to their divergent focuses.The former emphasizes epidemiology and clinical diagnosis and treatment, while the latter may pay more attention to the in-depth study of disease mechanisms and the development of drugs and vaccines for treating HFMD.
In the author analysis, Zhang Yong was the most prolific author in the field of HFMD (Table 2).However, when considering a comprehensive assessment of high-impact authors, Xu Wenbo stands out from the others.(Fig. 4B).Identifying high-producing authors helps evaluate their status and influence in the academic field.High-yield authors usually cooperate with high-impact authors to promote progress in HFMD research.Highly productive authors who publish many articles quickly can represent specific research directions and hotspots, inspire other researchers to accurately and quickly identify the research focus of HFMD, and promote the development and progress of this field.
Identifying high-producing journals is an important research direction in bibliometrics.Its significance lies not only in academic evaluation and ranking, but also in providing guidance and reference for academic research, supporting policy-making and decision-making, promoting academic communication and collaboration, and promoting the development and innovation in HFMD. [21]Our research findings indicate that in recent years, there have been several published articles on HFMD in specialized journals in the field of virology (Fig. 5 and Table 3), which suggests that the emphasis in HFMD-related studies has been on investigating the characteristics of disease-causing pathogens and prevention and treatment measures.High-producing journals usually have higher IFs and citation frequencies, which can be a reference for researchers when selecting journals to submit their work.
The analysis of keywords also revealed a close relationship among the topics of HFMD.In the visualization of keywords (Fig. 6A), a keyword network composed of 3 clusters is found.
According to these findings, virology, molecular biology and epidemiology, clinical diagnosis and treatment, prevention, and control are the main research fields in HFMD.The emergence of keywords is helpful to understand the current and future research trends in HFMD.Future research should focus on the biological characteristics, transmission mechanisms, risk factors, epidemiology, immune research, clinical efficacy, and specific treatment methods of the virus, to better prevent and control HFMD (Fig. 6B).However, although there are some vaccines and treatments for HFMD, there is still a need to develop specific treatments and rapid diagnostic methods.Future research should focus on the rapid clinical diagnosis and specific treatment methods of HFMD, to better prevent and control it.The morbidity and mortality of HFMD remain high worldwide.The epidemiological features and trends of HFMD may continue to be the focus of research, such as age and geographical distribution, seasonality, and climate change, to formulate and implement better prevention and control strategies. [22]The occurrence and spread of HFMD are closely related to the immune system, such as cellular immunity and humoral immunity.Vaccine research is still the most concerning issue in the world.Accelerating the development of effective vaccines is necessary to prevent and control HFMD. [23]n 2010, Solomon and Tom published a paper on "Virology, epidemiology, pathogenesis, and control of enterovirus 71" in the famous journal "The Lancet Infectious Diseases" (Table 4).Among the 1860 articles, this article is highly cited for its comprehensive report on the hot and cutting-edge human enterovirus 71 (EV71) issues, including virology, epidemiology, pathogenesis, and control methods.This study provides essential information for future researchers, and its reliability and methods contribute to its influence.The article's impact encourages global researchers to leverage their creativity, explore unknown information in the field, and contribute to studying HFMD.The 3 articles that began to break out in recent years focused on enteroviruses, HFMD, and the outbreaks of EV71 in the Asia-Pacific region (Fig. 7).The recent surge in interest and research on this subject can be attributed to several factors, namely, Increase in the incidence and severity of enterovirus infections.Over the past few years, there has been a surge in the number and severity of enterovirus infections, particularly in the Asia-Pacific region.[24] This trend urges people to pay more attention to understanding these viruses' life cycles and epidemiology and to formulate practical guidelines for diagnosis and treatment.[25,26] The emergence of new strains: Enterovirus mutates rapidly, and new strains can appear soon.Consequently, ongoing surveillance and research are required to understand the genetic diversity of these viruses and how they may evolve."Growing public health concerns: The increase in the incidence and severity of enterovirus infections" have led to growing public health concerns about these viruses.This urges researchers, healthcare providers, and policymakers to pay more attention to formulating effective prevention and control strategies.The recent surge in interest in and research on enterovirus can be attributed to many factors, including new strains, increased incidence and severity of infections, and growing public health concerns.The 3 articles analyzed provide insights into the enteroviruses' life cycle, diagnosis, treatment, and epidemiology.They can provide future research and public health work on controlling these infections.
There are some limitations.First of all, the analysis only included articles from the WoSCC and may ignore articles from other databases.Additionally, excluding non-journal and review articles during article screening may overlook other viewpoints.The article focuses on HFMD but pays little attention to viruses that cause the disease, which leads to an incomplete conclusion.

Conclusion
This study analyzed article metrics to examine publications related to HFMD and identified the most prolific journals, authors, and countries in this field.In future research, it would be beneficial to determine the current and potential future research hotspots, which can provide researchers with a more comprehensive range of choices.Our findings indicate that China is the most productive country.The Chinese Academy of Sciences is the most prolific institution, while the Chinese Center for Disease Control and Prevention is the most influential institution.China has a high prevalence rate of HFMD, making it a leading region for HFMD research.Our research will provide valuable information related to HFMD, and help researchers to detect and prevent this disease at an early stage.

a
Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medicine Sciences/School of Pharmacy/National Demonstration Center for Experimental (General Practice) Education, Xianning Medical College, Hubei University of Science and Technology, Xianning, China.

Figure 3 .
Figure 3. Visual analysis of the country with HFMD publications.(A) Index for the top 10 countries with HFMD articles; (B) average citations of articles from the top 10 HFMD countries; (C) total citations for the top 10 HFMD articles; (D) collaborative graph of at least 10 countries with HFMD articles.

Figure 4 .
Figure 4. Analysis of institutions and authors of HFMD-related publications.(A) Number of institutions with >30 HFMD publications; (B) authors with >20 HFMD publications.
focusing on HFMD and conducting related research.Moreover, advances in technology have led to more accurate identification of pathogens and analysis of infectious disease outbreaks, thus promoting related research, including HFMD.The current stable research trend of HFMD is driven by the continuous epidemic of the disease and the technical progress, although this trend has been somewhat influenced by the Corona Virus Disease 2019 (COVID-19) pandemic in the past 3 years.

Figure 6 .
Figure 6.Analysis of keywords of HFMD publications.(A) HFMD-related keywords that occur at least 50 times in total; (B) top 25 keywords with the highest intensity of HFMD outbreaks.

Table 2
The top 10 productive authors involved in HFMD research.

Table 3
The top 10 journals in number of publications related to HFMD.

Table 4
The top 10 high-cited references related to HFMD.